Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10(-7) M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P < 0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [3H]acetate into cholesterol) by up to 90% (P < 0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM's cholesterol synthesis by up to 70% (P < 0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10(-7) M Ang II for 18 h at 37 degrees C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10(-5) M), an AT1 blocker, but not PD 123319 (10(-5) M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.
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PMID:Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. 1053 81

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.
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PMID:[Genetic analysis of candidate gene polymorphisms in elderly hypertension]. 1055 62

Primary diastolic failure is typically seen in patients with hypertensive or valvular heart disease as well as in hypertrophic or restrictive cardiomyopathy but can also occur in a variety of clinical disorders, especially tachycardia and ischemia. Diastolic dysfunction has a particularly high prevalence in elderly patients and is generally associated, with low mortality but high morbidity. The pathophysiology of diastolic dysfunction includes delayed relaxation, impaired LV filling and/or increased stiffness. These conditions result typically in an upward displacement of the diastolic pressure-volume relationship with increased end-diastolic, left atrial and pulmo-capillary wedge pressure leading to symptoms of pulmonary congestion. Diagnosis of diastolic heart failure requires three conditions: (1) presence of signs or symptoms of heart failure; (2) presence of normal or slightly reduced LV ejection fraction (EF > 50%) and (3) presence of increased diastolic filling pressure. Assessment of diastolic function can be performed with several non-invasive (2D- and Doppler-echocardiography, color Doppler M-mode, Doppler tissue imaging, MR-myocardial tagging, radionuclide ventriculography) and invasive techniques (micromanometry, angiography, conductance method). Doppler-echocardiography is the most useful tool to routinely measure diastolic function. Different techniques can be used alone or in combination to assess LV diastolic function, but most of them are dependent on heart rate, pre- and afterload. The transmitral flow pattern remains the starting point, since it is easy to acquire and rapidly categorizes patients into normal (E > A), delayed relaxation (E < A), and restrictive (E >> A) filling patterns. Invasive assessment of diastolic function allows determination of the time constant of relaxation from the exponential pressure decay during isovolumic relaxation, and the evaluation of the passive elastic properties from the slope of the diastolic pressure-volume (= constant of chamber stiffness) and stress-strain relationship (= constant of myocardial stiffness). The prognosis of diastolic heart failure is usually better than for systolic dysfunction. Diastolic heart failure is associated with a lower annual mortality rate of approximately 8% as compared to annual mortality of 19% in heart failure with systolic dysfunction, however, morbidity rate can be substantial. Thus, diastolic heart failure is an important clinical disorder mainly seen in the elderly patients with hypertensive heart disease. Early recognition and appropriate therapy of diastolic dysfunction is advisable to prevent further progression to diastolic heart failure and death. There is no specific therapy to improve LV diastolic function directly. Medical therapy of diastolic dysfunction is often empirical and lacks clear-cut pathophysiologic concepts. Nevertheless, there is growing evidence that calcium channel blockers, beta-blockers, ACE-inhibitors and AT2-blockers as well as nitric oxide donors can be beneficial. Treatment of the underlying disease is currently the most important therapeutic approach.
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PMID:Diastolic heart failure. 1072 7

Recent studies have demonstrated that the renin-angiotensin system (RAS) participates in the processes of inflammation. An active component of this system, angiotensin II (Ang II), differentially regulates the production of oxyradicals, nitric oxide, prostaglandins, platelet-activating factors and bradykinins by acting through AT1 or AT2 receptor subtypes. Many of the physiological actions of Ang II mediated through AT1 and AT2 receptors are opposite and thereby show physiological antagonism to each other. In the present study, we evaluated the effect of locally administered Ang II, the ACE inhibitor captopril and the AT1 receptor antagonist losartan in the carrageenan model of acute inflammation. Local administration of losartan (10-50 micrograms/paw) or Ang II (0.2-1 microgram/paw) alone did not induce inflammation, but significantly enhanced the carrageenan-induced edema in a dose-dependent manner. Coadministration of subeffective doses of losartan (10 micrograms/paw) and Ang II (0.2 microgram/paw) significantly potentiated the carrageenan-induced inflammation. In conclusion, the present study predicts that Ang II might be formed locally during carrageenan-induced acute inflammation. Potentiation of the Ang II effect in carrageenan-induced inflammation by losartan may be mediated through over-stimulation of unblocked AT2 receptors or due to stimulation of inflammatory pathways by unknown mechanisms.
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PMID:AT1 receptor antagonism enhances angiotensin-II-facilitated carrageenan-induced paw edema. 1125 35

The A II antagonists (RA II antagonists) are a new group of anti-hypertensive drugs with five years of clinical use. They were investigated after the knowledge of independent ways to get angiotensin II. They block AT1 receptor. It's possible that, after AT1 block, the high plasmatic levels of AII stimulate the AT2 receptors with vasodilation and anti-proliferative activity. We are waiting for the results of several big prospective studies with RA II antagonists on cardiovascular morbidity and mortality. At present time, the first indication for its use is the appearance of cough when taking ACE inhibitors. The association of ACE inhibitors and RA II antagonists can improve some clinical conditions like dilated hypertensive cardiopathy, nephropathy or refractory hypertension.
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PMID:[ACE inhibitors versus AR II antagonists. Their role in arterial hypertension]. 1130 10

This review deals with similarities and differences between the effects of ACE inhibitors and AT1-receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1 blockers arise from two mechanisms: the reduction of the AT1 receptor mediated response and the increase in plasma levels of Ang II through the AT1-receptor blockade, which leads to increased stimulation of the AT2 receptor (the so-called yin-yang effect). Both ACE inhibition and AT1-receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1 receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1-receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long-term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.
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PMID:Angiotensin receptor blockers and the kidney: possible advantages over ACE inhibition? 1131 2

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.
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PMID:Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. 1132 78

Angiotensin II(AII) accelerates the progress of cardiovascular diseases. This was proved by the fact that the blockade of renin-angiotensin system provided clinical benefits for patients with cardiovascular diseases. This review focuses on the differences between AT1-receptor antagonist and ACE inhibitor in basic and clinical aspects. Beside decreased AII concentration, increased tissue bradykinin concentration may contribute to the beneficial effect of ACE inhibitor, on the other hand, this increases the rate of cough to decrease the compliance. Increased AII concentration by AII receptor antagonist may antagonize the binding of the drug as well as stimulate AT2 receptor subtype. ACE inhibitor can not block the effect of non-ACE AII formation, but AII receptor does. These differences should be considered for their clinical use.
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PMID:[Comparison between AngII receptor antagonist and ACE inhibitor]. 1139 5

After recalling the fundamental importance of ACE inhibitors in the treatment of heart failure, the author analyzes the scientific evidence supporting the use of beta-adrenergic blockers in the treatment of this syndrome. He describes the complications involved in prescribing these drugs for patients in functional class IV and reviews the current literature on the problem. He then considers the possibility of beta-blockers (particularly carvedilol) being used instead of ACE inhibitors. He reviews the conclusions of studies on the benefits of adding an AT1 receptor antagonist to ACE inhibitor therapy, including the results of the RESOLVD studies. He also concludes that there is no evidence that AT2 receptor antagonists are as good as or better than ACE inhibitors in the treatment of heart failure.
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PMID:[Options in drug combinations]. 1140 73

ACE (Angiotensin Converting Enzyme) inhibitors and angiotensin II type 1 receptor antagonists increase the effective renal plasma flow dose dependently, whereas glomerular filtration rate does not change. Both substances reduce dose dependently arterial blood pressure, glomerular capillary pressure and proteinuria and are probably comparably renoprotective due to haemodynamic and non-haemodynamic (e.g. antiproliferative) effects. These data indicate that the renoprotective effects of ACE inhibitors and angiotensin II receptor antagonists are the results of inhibition of angiotensin II and not due to inhibition of bradykinin degradation. Several studies suggest an additive renoprotective effect of ACE inhibitors and angiotensin II receptor antagonists. However, controlled clinical studies are lacking. Experimental data suggest that the combination of AT1 and AT2 receptor blockers or treatment with ACE inhibitors reduce more effectively inflammatory cell infiltration into the kidney than angiotensin II type 1 receptor antagonists alone. Long-term clinical trials using angiotensin II type 1 receptor antagonists are needed before these substances can be recommended as comparably renoprotective as ACE inhibitors.
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PMID:[Angiotensin II type-1-receptor antagonists from the viewpoint of nephrology]. 1145 Jan 64


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